Asymptomatic cerebral calcification apreviously ... · ofI...

Postgrad Med J (1991) 67, 147 - 153 i) The Fellowship of Postgraduate Medicine, 1991

Asymptomatic cerebral calcification - a previouslyunrecognized feature

Muoi M. Arnold' and Louis Kreel2

'Department ofAnatomical and Cellular Pathology, 2Department ofDiagnostic Radiology and OrganImaging, Prince of Wales Hospital, The Chinese University ofHong Kong, Hong Kong

Summary: While investigating the radiological appearances of globus pallidus calcification in anautopsy case, cortical-pia mater calcification was detected. There was no documentation of its existence inthe literature of radiology, neurology and neuropathology. To establish its incidence and clinicalsignificance, 20 consecutive autopsy brains (15 males, 5 females, age 32-73 years, mean age 56.7) werestudied with high resolution radiography and histology. Clinical records, autopsy findings, in-life plainskull films and computed tomography of the brain (if available) were reviewed. Radiologically, thecalcifications appeared as 1-2 mm irregular spots or tiny pin-point opacities in the pia mater andsubcortical regions, either unilaterally or bilaterally in the frontal (15 cases), temporal (15), parietal (3)and occipital lobes (1). Similar calcification was detected in 1 of the 3 in-life computed tomographic scansavailable. Histologically, these cortical-pia mater calcifications were extracellular amorphous calcifiedmasses of various sizes in necrotic neural tissue, frequently associated with microscopic haemorrhage andhypoxic neuronal changes in the adjacent brain tissue. Blood vessels in the region were not hyalinized orcalcified. The occurrence was not related to age. Hospital stay was < 7 days in 14 and < 30 days in 2;50% of patients died within 48 hours after admission. None of the patients had records of long termcytotoxic chemotherapy, radiotherapy or central nervous system infection. Two had stroke, one hadcerebellar atrophy and one mild hypercalcaemia. The high incidence ofcalcifications in the temporal lobes,while asymptomatic, suggests that cortical calcification may be a pointer to the aetiology of idiopathicepilepsies in the elderly.

Introduction

The normal or asymptomatic intracranial calci-fications have been well documented by plain filmsof the skull and subsequently computed tomo-graphy (CT) and include pineal, calcifications inthe habenula, choroidal plexus, falx and Pacchion-ian granulations as well as the basal gangliaespecially in the globus pallidus. While investi-gating the appearances of globus pallidus calcifi-cation of an autopsy case by high resolutionradiography for correlation with in-life CT, cor-tical calcification was detected. Subsequently, atotal of20 autopsy brains were examined, ofwhoma large number were found to have this type ofcalcification. A literature search failed to elicit asimilar report.

Materials and methods

Twenty consecutive 20% formalin fixed humanautopsy brains were examined by plain film radio-

graphy and relevant areas subjected to histology.Each brain was sectioned at 1 cm intervals in theaxial plane corresponding to a computed tomo-graphy examination. The brain slices were radio-graphed with an overcouch tube using a standardscreen-film combination. The films were viewedand brain sections chosen for high resolution softtissue radiography using a mammography unit(Figure 1). Having localized the calcifications, therelevant area of brain was removed and slices ofapproximately 1.5 -2 mm thick were cut parallel tothe axial plane and again radiographed (Figure 2).Representative thin tissue blocks were processedfor histological examination.The various types and sites of calcification were

recorded as seen on the initial films, the highresolution films of the axial brain slices and of theselected 1.5-2 mm thick tissue sections. Specialattention was paid to pial and cortical calcification,but other calcifications were also recorded when

Siemen's mannomat E with a molybdenum tube usingKodak Min-R (single back) screen with Kodak Ortho M(single coated film).

Correspondence: Muoi M. Arnold, M.D. (Saigon)Accepted: 15 October 1990

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148 M.M. ARNOLD AND L. KREEL

Figure 1 On a high resolution soft tissue film of a I cmthick section, there are cortical calcifications particularlyin the temporal lobe but also in the frontal lobes. Some ofthe calcifications are quite large, i.e. about 1-2 mm, butmost are considerably smaller and more numerous.

present including pineal, habenula, choroidal andglobus pallidus.The histology sections from all brains were

randomized, labelled with a code number, and readby the pathologist. Notes were taken on themorphology of calcification, whether it was intra-or extracellular, its location in the nervous tissue,pia mater, blood vessel wall, and associated tissuechanges such as necrosis, neuronal loss andhaemorrhage. The pathological findings were theninterpreted in the light of radiological findings,clinical history and autopsy findings.The clinical case notes were carefully scrutinized

for central neurological signs and symptoms andthe autopsy examinations of the brains were noted.

Results

Sex and age distribution (Table I)

There were 15 males and 5 females, 11 were underthe age of60, the youngest, a female, was 32 and theoldest, a male, was aged 73.

Figure 2 In similar type radiograph of a 1.5 mm thicktissue block taken for histology the calcifications areclearly within the cortex as well as on the surface. Thelarge and small calcifications can be distinguished.

Length ofhospital stay prior to death (Table I)

Ten patients (50%) were in hospital for less than 48hours and 14 (70%) less than 1 week. Only onepatient was in for 1 month.

Clinical background and cause ofdeath (Table I)

No common clinico-pathological factor emergedfrom a scrutiny of the notes or from the autopsy.There were 4 patients with myocardial infarction, 4with pneumonia or bronchopneumonia, 5 withtuberculosis, 4 with a variety of infections, and 5with malignancies (all 3 lymphomas were post-mortem diagnoses). No patient had received cran-ial radiotherapy or prolonged multiple cytotoxicchemotherapy. Serum calcium level was availablein 12 patients. The adjusted calcium was withinnormal limits in 8 cases, low in 3 and slightlyincreased in 1 (patient No. 18). Phosphate levelswere normal in all cases. Only 4 patients hadclinical neurological symptoms and signs: 2 withstroke (Nos. 11, 12), 2 with severe hypoxic braindamage (Nos. 8, 13) confirmed by brain CT, and 1with lymphoma (No. 17) presented with acuteconfusion and fever of unknown origin.



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Radiographic calcifications (Table I)

Cortical-pia mater calcification could be identifiedin all cases on the radiographs. In 16 the calci-fication appeared sufficiently deep to be confidentthat it was in the cortex and was confirmed on thinslices. The calcifications appeared to be either spotsof I -2 mm or tiny pin-point calcifications (Figures1 and 2). The calcifications occurred most com-monly in the frontal region and were frequentlybilateral (13 cases) and symmetrical (8 cases).Globus pallidus calcification was found in 4 casesaged 32, 51, 68 and 73 years. Arterial calcificationin 14, pineal in 9, habenular in 9 and in the choroidplexus in 15. CT brain scans were performed in-lifeon 3 of these patients, these scans were reviewedand in one there appeared to be similar corticalcalcifications (Figure 3a,b).

Pathology

On gross examination all but 3 cases were normal.Cerebral haemorrhage in the thalamo-striate areawas present in 2 and cerebellar atrophy in 1 andgrittiness during cutting occurred in only 2 brains,both with heavy blood vessel wall calcification inthe basal ganglial region. Laminar necrosis was notapparent and cortical-pia mater calcifications werenot visible.

Histologically, there were two patterns of calci-fication in 89 sections, the peripheral pattern(cortical-pia mater) and the central pattern (in thebasal ganglia).The cortical-pia mater calcifications were com-

posed of large amorphous patches of calciumdeposit of various sizes, shapes and density innervous tissue (Figure 4) in the deep layers of greymatter or in the perivascular spaces ofthe pia materand Virchow's spaces, and frequently associatedwith microscopic haemorrhages. Hypoxia neuro-nal changes were evident in the preserved areas.There was no blood vessel calcification in theregion.

In the central pattern there were small spherulesof various sizes in the extracellular spaces oraround capillaries and conglomerations of sphe-rules formed multilobated calcifications (Figure 5).No tissue degeneration was visible on light micro-scopy. Calcification in the media of blood vesselswas common.

Discussion

Soft tissue calcification is usually classified asdystrophic and metastatic, the latter said usually tobe associated with a metabolic abnormality espec-ially hypercalcaemia. Most intracranial calcifi-cations such as pineal, choroid plexus, falx cerebri

a

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Figure 3 a, There are a small number of large calcifiedspots in the right posterior parietal region and smallerones on the left. The bilateral calcifications in the choroidplexus stand out more clearly, being contrasted againstthe air in the lateral ventricles of the 1 cm thick brainsection. b, A CT section of the same patient at approxi-mately the same level shows small densities (arrow) in thesame region suggesting the presence of calcifications.

and globus pallidus are common, well recognized,more frequent in the middle aged and elderly, andare considered as 'physiological' dystrophic cal-cification.' Pathological dystrophic calcification isless common but has well established associations



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Figure 4 In cortical-pia mater calcifications, both fine,granular and coarse irregular calcium deposits are presentin the necrotic brain tissue. The adjacent neural tissueshows hypoxic changes (Haematoxylin & eosin, x 170).

Figure 5 In the basal ganglia, calcification appears as

tiny spherules (large arrows) surrounding capillaries andscattered in the neuropil (small arrows) (Haematoxylin &eosin x 170).

with parasitic infestations, infections, particularlywith tuberculosis and cytomegalic virus, previoushaemorrhage and tumours. Since 1975 there hasbeen a spate of communications concerning cyto-toxic chemotherapy and radiotherapy as a cause ofcerebral dystrophic calcification in children withacute lymphoblastic leukaemia.2-5 Encephalitis6and Fahr's disease7'8 and meningio-angiomatosis9have also received attention. None of the cases

presented in our series had evidence to suggest any

of these conditions.The cortico-pia mater calcification described in

this paper has the features of dystrophic calci-fication being associated with degenerate nervous

tissue and microscopic haemorrhages. Histologic-ally, the cortical-pia mater calcifications are large,randomly distributed, irregular masses with no

regional blood vessel calcification, in contrast tothe predominantly perivascular tiny calcospherulesand heavy blood vessel calcification in our globuspallidus calcification group and in most of the

reported cases cited. A progressive microangio-pathic process appears to be the main pathogeneticfactor in the latter group. In the former group, theanatomical site, necrosis of the deep layers of thegrey matter, and associated microscopic haemorr-hage are suggestive of hypoxic laminar necrosisfrom a global ischaemia in the central nervoussystem; '0' however, calcification is not mentioned.Clinically, only one patient had a known period ofhypoxia though possibly the patients with cardio-vascular disease may have been similarly affected.

It is most unlikely that the patients who diedsoon after admission could have produced cerebralcalcifications associated with their acute illnessesand only two patients had cerebral haemorrhageand one cerebellar atrophy. These previous centralnervous system conditions were not a particularfeature either clinically or at autopsy.

Whilst it is surprising that a literature searchgoing back to 1965 and a review of severalneuropathology and neurology textbooks foundno description of similar brain calcifications, thismay be because it is considered clinically irrelevant.As far as we could determine, there were no signs orsymptoms to suggest the presence of these abnor-malities. Also, with routine autopsy brain examina-tion without radiographic examination of the brainslices, the cortical-pia mater calcifications wouldhave remained undetected as they are not visible tothe naked eye.As the temporal lobe was so commonly involved

it is just possible that these calcifications may be apointer to the aetiology of idiopathic epilepsy.Epidemiological surveys suggest an increased inci-dence of idiopathic epilepsy with age'2 up to 77 per100,000 in those over 60 years old'3 and thesecalcifications may prove to become more markedwith age, possibly being accumulated after eachepisode of severe illnesses.

It is, however, not surprising that these calcifi-cations are not visible on computed tomography asthey are small and close to the bone and areunlikely to be shown by magnetic resonance imag-ing as calcification produces signal void.The calcifications in the globus pallidus are well

recognized and, while of interest in their own right,are only marginally relevant to this communica-tion, the investigation having been started becauseof its recognition on CT and an attempt to show thecalcification in greater detail.

Acknowledgements

We would like to thank Mr Thomas Fung of MediaServices, Chinese University of Hong Kong (Prince ofWales Hospital), and Miss Sanny Chan for secretarialservices.



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References

1. Water, J.B. & Israel, M.S. Calcium metabolism and hetero-topic calcification. In: Water, J.B. & Israel, M.S. (eds)General Pathology. Churchill Livingstone, Edinburgh, 1987,p. 499.

2. Borns, P.F. & Rancier, L.F. Cerebral calcification in child-hood leukemia mimicking Sturge-Weber Syndrome. Am JRoentgenol 1974, 122: 52-55.

3. Flament-Durand, J., Ketelbant-Balasse, P., Maurus, R.,Regnier, R. & Spehl, M. Intracerebral calcifications appear-ing during the course of acute lymphocytic leukemia treatedwith methotrexate and X-rays. Cancer 1975, 35: 319- 325.

4. Price, R.A. & Birdwell, D.A. The central nervous system inchildhood leukemia. III. Mineralizing microangiopathy anddystrophic calcification. Cancer 1978, 42: 717-728.

5. Muller, K.M., Menne, R., Bachmann, K.D. & Grobe, H.Calcified cerebral necrosis following ALL therapy. J CancerRes Clin Oncol 1981, 102: 81-91.

6. Ishii, T., Matsushita, M. & Hamada, S. Characteristicresidual neuropathological features of Japanese B ence-phalitis. Acta Neuropathol 1977, 38: 181-186.

7. Bowman, M.S. Familial occurrence of 'idiopathic' calcifi-cation of cerebral capillaries. Am J Pathol 1954, 30: 87-97.

8. Friede, R.L., Magee, K.R., Mich, A.A. & Mack, E.W.Idiopathic nonarteriosclerotic calcification of cerebralvessels. Arch Neurol 1961, 5: 279-286.

9. Halper, J., Scheithauer, B.W., Okazaki, H. & Laws, E.R.Meningio-angiomatosis: a report of six cases with specialreferences to the occurrence of neurofibrillary tangles. JNeuropathol Exp Neurol 1986, 45: 426-446.

10. Mergner, W.J. & Trump, B.F. Hemodynamic disorders. In:Rubin, E. & Farber, J.L. (eds) Pathology. J.B. Lippincott,Philadelphia, 1988, p. 273.

11. Vogel, F.S. The central nervous system. In: Rubin, E. &Farber, J.L. (eds) Pathology. J.B. Lippincott, Philadelphia,1988, pp. 1433-1434.

12. Hauser, A. & Kurland, L.T. The epidemiology of epilepsy inRochester, Minnesota, 1935 through 1967. Epilepsia 1975,16: 1-66.

13. Luhdorf, K., Jensen, L.K. & Plesner, A. Etiology of seizuresin the elderly. Epilepsia 1986, 27: 458-463.



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